The World Journal of Biological Psychiatry, 2010; 11(S1): 29–30

ISSN 1562-2975 print/ISSN 1814-1412 online © 2010 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)DOI: 10.3109/15622971003637702

CONCLUSION

Pharmacological intervention in slow-wave sleep: A novel approach to the management of insomnia?

The articles in this supplement include data on a wide range of aspects of sleep and bring together a number of recent fi ndings showing advances in the under-standing of slow-wave sleep (SWS) in particular.

The article by Pierre-Hervé Luppi discussed the latest fi ndings on the mechanisms by which the brain switches between waking, non rapid eye movement (REM) sleep, and REM sleep (Luppi 2010). He reviewed the evidence that the cortical activation which characterises waking is brought about by a number of “waking” systems at different subcortical levels, including the serotonergic, noradrenergic, cholinergic, and hypocretin systems (Moruzzi and Magoun 1949; Moruzzi 1972; Fort et al. 2009). The activity of these systems shows marked changes across the vigilance states. A prime example is the fi ring rate of serotonergic neurons, which is high dur-ing wakefulness, lower during SWS and near zero during REM sleep. This inhibition of serotonergic neurons is brought about by the inhibitory neu-rotransmitter γ -aminobutyric acid (GABA). Sub-stantial evidence has accumulated that the switch between waking to nonREM sleep involves the release of GABA by neurons in the ventrolateral pre-optic nucleus (VLPO) (Gervasoni et al. 1998; Ger-vasoni et al. 2000). The VLPO increases its fi ring rate at sleep onset and continues to discharge selectively throughout nonREM sleep.

The VLPO thereby imposes inhibition not only on the dorsal raphe but on all wake centers.

Pierre Maquet provided on overview of recent advances in neuroimaging in relation to sleep and in particular, SWS (Maquet 2010). Much of our previ-ous knowledge on brain activity during SWS was based on positron emission tomography, which has a relatively low temporal resolution. This technique gave the appearance of reduced activity during SWS (Maquet 2000). However, images with a relatively high spatial and temporal resolution can be acquired using functional magnetic resonance imaging (fMRI), which measure brain activity based on changes in blood oxygen level (Bandettini 2009). Combined use of this technique with electroencephalography shows

increased activity in a number of brain regions during the up-state of the slow oscillation as well as during spindle activity. Some of these brain areas are involved in processing of memories (Schabus et al. 2007; Dang-Vu et al. 2008).

In the third article, Jan Born discussed the role of SWS in the consolidation of declarative memory (Born 2010). Declarative memories are simultane-ously encoded in the neocortex and hippocampus, with the encoding being strongest in the hippocam-pus. Slow oscillations during SWS originate in the neocortex and are thought to be related to informa-tion encoding during wakefulness (Wilson and McNaughton 1994; Sutherland and McNaughton 2000). The model for declarative memory consolida-tion presented in this article suggests that, during SWS, the neocortical slow oscillations accompanied by hippocampal sharp-wave ripples and thalamocor-tical spindles, stimulate the reactivation of newly encoded material in the hippocampus and this stim-ulates the transfer of reactivated memory to the neocortex (Born et al. 2006; Marshall and Born 2007).

In the fi nal article, the factors that modify SWS, and may lead to SWS defi ciency are discussed in relation to insomnia and its management (Dijk 2010). SWS is not only reduced in older people but also in situations of high “apprehension”. Under non-pharmacological conditions, less SWS is associ-ated with poorer sleep maintenance. Suppression of SWS/SWA by acoustic stimulation leads to an increase in daytime sleep propensity, suggesting that SWS/SWA plays an important role in recovery pro-cesses during SWS. SWA is suppressed by benzodi-azepines and the “Z drugs”, which are the most commonly prescribed agents for the management of insomnia (Lancel 1999). However, in healthy volun-teers, SWA enhancement is seen with a number of agents, including the GAT-1 inhibitor tiagabine (Mathias et al. 2001), the GABA-A modulator gaboxadol (Walsh et al. 2007; Dijk et al. 2009), and the 5-hydroxytryptamine-2A antagonists seganserin and eplivanserin (Dijk et al. 1989; Landolt et al.

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30 G. Hajak

Gervasoni D, Darracq L, Fort P, Souliere F, Chouvet G, Luppi PH. 1998. Electrophysiological evidence that noradrenergic neurons of the rat locus coeruleus are tonically inhibited by GABA during sleep. Eur J Neurosci 10(3):964–970.

Gervasoni D, Peyron C, Rampon C, Barbagli B, Chouvet G, Urbain N, et al. 2000. Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons. J Neurosci 20(11):4217–4225.

Lancel M. 1999. Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists. Sleep 22(1):33–42.

Landolt HP, Meier V, Burgess HJ, Finelli LA, Cattelin F, Achermann P, et al. 1999. Serotonin-2 receptors and human sleep: effect of a selective antagonist on EEG power spectra. Neuropsychopharmacology 21(3):455–466.

Luppi PH. 2010. Neurochemical aspects of sleep regulation with specifi c focus on slow-wave sleep. World J Biol Psychiatry 11(Suppl 1):4–8.

Maquet P. 2000. Functional neuroimaging of normal human sleep by positron emission tomography. J Sleep Res 9(3):207–231.

Maquet P. 2010. Understanding slow-wave sleep through neu-roimaging. World J Biol Psychiatry 11(Suppl 1):9–15.

Marshall L, Born J. 2007. The contribution of sleep to hippoc-ampus-dependent memory consolidation. Trends Cogn Sci 11(10):442–450.

Mathias S, Wetter TC, Steiger A, Lancel M. 2001. The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects. Neurobiol Aging 22(2):247–253.

Moruzzi G. 1972. The sleep-waking cycle. Ergeb Physiol 64:1–165. Moruzzi G, Magoun HW. 1949. Brain stem reticular formation

and activation of the EEG. Electroencephalogr Clin Neuro-physiol 1(4):455–473.

Schabus M, Dang-Vu TT, Albouy G, Balteau E, Boly M, Carrier J, et al. 2007. Hemodynamic cerebral correlates of sleep spindles during human non-rapid eye movement sleep. Proc Natl Acad Sci USA 104(32):13164–13169.

Sutherland GR, McNaughton B. 2000. Memory trace reactiva-tion in hippocampal and neocortical neuronal ensembles. Curr Opin Neurobiol 10(2):180–186.

Walsh JK, Deacon S, Dijk DJ, Lundahl J. 2007. The selective extra-synaptic GABAA agonist, gaboxadol, improves traditional hyp-notic effi cacy measures and enhances slow wave activity in a model of transient insomnia. Sleep 30(5):593–602.

Wilson MA, McNaughton BL. 1994. Reactivation of hippo-campal ensemble memories during sleep. Science 265(5172): 676–679.

1999). Some of these compounds have also been shown to increase SWS in insomnia.

GÖRAN HAJAK Guest Editor

Correspondence:Department of Psychiatry, Psychosomatics and

PsychotherapyUniversity of Regensburg

Universitätsstrasse 84D-93053 Regensburg

GermanyTel: +49 941 941 2011

E-mail: goeran.hajak@medbo.de

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Born J. 2010. Slow-wave sleep and the consolidation of long-term memory. World J Biol Psychiatry 11(Suppl 1):16–21.

Born J, Rasch B, Gais S. 2006. Sleep to remember. Neuroscientist 12(5):410–424.

Dang-Vu TT, Schabus M, Desseilles M, Albouy G, Boly M, Darsaud A, et al. 2008. Spontaneous neural activity during human slow wave sleep. Proc Natl Acad Sci USA 105(39):15160–15165.

Dijk DJ. 2010. Slow-wave sleep defi ciency and enhancement: implications for insomnia and its management. World J Biol Psychiatry 11(Suppl 1):22–28.

Dijk DJ, Beersma DG, Daan S, van den Hoofdakker RH. 1989. Effects of seganserin, a 5-HT2 antagonist, and temazepam on human sleep stages and EEG power spectra. Eur J Pharmacol 171(2–3):207–218.

Dijk DJ, James L, Peters S, Walsh J, Deacon S. 2009. Sex differences and the effect of gaboxadol and zolpidem on EEG power spectra in NREM and REM sleep. J Psychopharmacol E pub ahead of print.

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